Process of oxidizing 3, 11-diketo-17-hydroxypregnanes and product obtained thereby



Patented July 25, 1950 l t R PROCESS OF OXIDIZING 3,11-DIKE'IO-17- HYDROXYPEEGNANES AND PRODUCT OBTAINED vTHEREBY Lewis Hastings Sarett, Princeton, N. J., assignor to Merck & 00., Inc., Rahway, N. J., a corporation of NewJersey No Drawing. Application'August 15, 1946,

' Serial No. 690,823

.6 claims-1 (01. 260-3973) 2 This invention is concerned generally with resenting the valence bond in the cis configuranovel chemical compounds of the cyclopentanoe tion. I dimethylpolyhydrophenanthrene series and to It is now found that the 3,11,1'7-triketo-eti0choprocesses of preparing the same; more particlane and 3,11,20-triketo-17-hydroXy-pregnane ularly it relates to 3,11,17-triketo-etiocholane and 5 can be synthetized by reactions indicated ge- 3,11,20-tri-keto-l'l-hydroxy-pregnane, useful as nerically as follows: intermediates in the production of compounds CH3 having the physiological activity of adrenal certex hormones, and to syntheses of these com & pounds from readily available'starting naterials. HOH

The 3,11,17-triketo-etiocholane and the 3,11,20- triketo-l'l-hydroxy-pregnane, subject of this application, can be represented by the following structural formulae:

19 CH3 0 i (1)} ozidlzing 11: n agent o O p O C I I 1 C11 C13 16GB: CH3

Ha I I f CH3 14 15 y GHCH2 CH3 C A 7 B I k I v 5 7011; I l

19 CH3 I O: v

21011: w '30 H i 20 =0 The reactions indicated above are conducted as H, follows: The starting material, 3,11-dil eto-17,20- g R dihydroxy-pregnane (1), can be prepared from 011 13 160112 the readily available bile acid, desoxycholicacid, 36 by processes disclosed in my copending applica 13: H 1 6 H tions, Serial No. 649,760, filed February'23, 1,946 /1\ /9\ (which is a continuation-in-part of application H202 010 80H Serial No. 605,194, filed July 14, 1945, now aban- A I B l 'doned); Serial No. 687,982, filed August 2, 194's, mm 40 nowPate'nt'No. 2,505,838, and Serial No.-'683,427, \4/ \6/ filed June 13, 1946, now Patent No. 2,493,780.

g v This starting'material is reacted with an oxidizing agent to produce a mixture comprising These formulae, for purposes of convenience are 3,1L17riketmetiocho1ane and 311, 20, tfi hereinafter reproduced below in the abbreviated t '17 form. 0.11: 4 According to the presently invented process, CH3 CH8; '3,11-diketo-17,20-dihydroXy-pregnane, which can be r' eene the ill CH3 0 CH3 0:0 form s t d by a; owing structural l OH 5 CH3 CH3 $11011 0 011 j 0 o 65 H H In the following description of the invention, (1) the stereochemical relationship of rings A and B is indicated in the formulae by a solid line rep- I H is reacted with an oxidizing agent, as for example, chromic acid, periodic acid, sodium periodate, lead tetracetate, and the like. acid is employed as the oxidizing agent, the product comprises a mixture of 3,11,20-triketo-17- hydroxy-pregnane and 3,l1,17-triketo-etiocho-. lane. The reaction is conveniently carried out in aqueous acidic solution but other media can be employed if desired. It is presently preferred to employ an aqueous solution of a lower aliphatic acid, such as aqueous acetic acid, aqueous propionic acid, and the like. The mixture is allowed to react for a time sufficient to substantially com plete the oxidation reaction; when aqueous chromic acid is added to an acetic acid solution of the aforementioned starting materials and the mixture allowed to react at about 20 to C5, the time required for substantially complete reaction is about 3 to 4 hours.

A reducing agent, such as sodium sulfite, sodium bisulfite, and the like, is added to reduce any excess oxidizing agent remaining unreacted and the resulting solution is evaporated substantially to dryness to volatilize any aliphatic organic acid used during the oxidation reaction. The residual material is diluted with water and the cyclopentanodimethylpolyhydrophenanthrene product extracted therefrom by means of a chlorinated hydrocarbon solvent such as chloroform, ethylene dichloride, and the like. The chlorinated hydrocarbon extract is shaken with a mild aqueous alkaline solution, then with water and evaporated to dryness to produce a mixture of 3,11,17-triketo-etiocholane and 3,11,20-triketo- I'I-hydroxy-pregnane. These compounds can be separated from each other and isolated in substantially pure form by any convenient means; it is presently preferred to effect said separation by chromatographic absorption from ether solution of the compounds employing activated alumina.

The following example illustrates a method of carrying out the presently invented process but it is to be und rstood that this example is given by way of illustration and not of limitation.

Example sufficient sodium sulfite to destroy excess chromic acid; the resulting solution is then evaporated to dryness under reduced pressure, the residue is diluted with water and extracted with chloroe form. The chloroform extract is washed first with dilute aqueous potassium carbonate solution When chromic and then with water and is then evaporated to 4 chloroform andis separated chromatographically using activated alumina. The first fractions contain 3,11,17-triketo-etiocholane which is purified by recrystallization from dilute methanol and from ether; M. P. 134-135" C. (corn) a =+155 (acetone).

The latter fractions from the chromatogram contain 3,11,20 triketo l7 hydroxy-pregnane which is purified by crystallization from dilute acetone; M. P. 205-206 C. (corn); a (acetone).

I claim:

1. The process which comprises reacting 3,11- diketo 17,20 dihydroxy pregnane with a considerable excess of an oxidizing agent selected from the class which consists of chromic acid,

periodic acid, sodium periodate and lead tetraacetate, to produce a mixture comprising 3,11,17- triketo etiocholane and 3,11,20 triketov l7 hydroxy-pregnane.

2. The process which comprises reacting 3,11- diketo-17,20-dihydroxy-pregnane with chromic acid to produce a mixture containing 3,11,17- triketo etiocholane and 3,11,20 triketo 1'7 hydroxy-pregnane and isolating substantially pure 3,11,17 triketo etiocholane and 3,11,20 triketo-17-hydroxy pregnane therefrom.

3. The process which comprises reacting 3,11,20-triketo-17-hydroxy-pregnane with a considerable excess of an oxidizing agent selected from the class which consists of chromic acid, periodic acid, sodium periodate and lead tetraacetate, to produce 3,11,17-triketo-etiocholane.

4. The process which comprising reacting 3,11- diketo-17,20-dihydroxy-pregnane with chromic acid to produce 3,11,20-triketo-l7-hydroxy-pregnane.

5. The process which comprises reacting 3,11-

diketo-17,20-dihydroxy-pregnane with chromic acid in glacial acetic acid to produce a mixture containing 3,11,17 triketo etiocholane and 3,11,20-triketo-l'l-hydroxy-pregnane; and separating these compounds from each other by chromatographic absorption.

6. 3,1120 triketo 17 hydroxy pregnane, having a melting point of about 205-206" C. and an a approximately equal to +75 in acetone.

LEWIS HASTINGS SARETT.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,256,500 Serini Sept. 23, 194.1 2,275,790 Miescher Mar. 10, 1942 2,389,325 Reichstein Nov. 20, 1945 OTHER REFERENCES Mason, Jour. Biol. Chem, 124, pages 461, 469 (1938). 

1. THE PROCESS WHICH COMPRISES REACTING 3,11DIKETO - 17,20 - DIHYDROXY - PREGNANE WITH A CONSIDERABLE EXCESS OF AN OXIDIZING AGENT SELECTED FROM THE CLASS WHICH CONSISTS OF CHROMIC ACID, PERIODIC ACID, SODIUM PERIODATE AND LEAD TETRAACETATE, TO PRODUCE A MIXTURE COMPRISING 3,11,17TRIKETO - ETIOCHOLANE AND 3,11,20 - TRIKETO - 17 HYDROXY-PREGNANE. 